tbuckley/cabot-search huggingface dataset:
Clinical utility of genomic recurrence risk stratification in early, hormone receptor–positive, human epidermal growth factor receptor 2–negative breast cancer.
Authors: Khalil Choucair, Seth Joel Page, Bassam Ibrahim Mattar, Christopher Dakhil, Nassim H. Nabbout, Jeremy Michael Deutsch, Quoc Van Truong, Phu Van Truong, Dennis Frederic Moore, Michael W. Cannon, K. James Kallail, Joseph A Moore, Shaker R. Dakhil, Radwan Diab, Syed Kamran, Pavan S. Reddy
Journal: Journal of Clinical Oncology (2022)

546 Background: RNA-based genomic assessment of recurrence risk is used to estimate chemotherapy benefit in patients with hormone-receptor positive (HR+)/Human Epidermal Growth Factor 2-negative ( ERBB2-) breast cancer (BC). While originally validated in patients who met established clinicopathologic guidelines for consideration of adjuvant chemotherapy, it is virtually used in all patients with early HR+/ ERBB2- BC regardless of clinical recurrence risk. Methods: We conducted a retrospective chart review of adult patients with early-stage (T1-3; N0; M0) HR+/ ERBB2- BC who underwent genomic risk assessment of recurrence using the Oncotype DX (Exact Sciences) 21-genes assay, between January 2015 and December 2020. Clinicopathologic features were collected to assess the clinical recurrence risk. A low clinical risk score (CRS) was defined as a tumor size ≤ 3 cm in diameter with histologic grade 1, or ≤ 2 cm with grade 2 or ≤ 1 cm with grade 3. A composite risk score of distant recurrent (RRS), derived from a COX model using data from the SOFT and TEXT trials ( https://rconnect.dfci.harvard.edu/CompositeRiskSTEPP/ ), was also computed for 374 patients for whom clinical data was available. RRS &gt; 1.42 was defined as high. High genomic risk of recurrence was defined as a score (GRS) ≥25. The data was collected under IRB approval. Results: A total of 517 patients with early-stage disease were referred for genomic testing, and clinical data was available for 501 of them. Median age was 69 years (IQR=13), median tumor size 1.03 cm (IQR=0.9), and grade 2 histology (57.49%) was the most common. Results of recurrence risk, using the 3 prognostication methods, are summarized in Table. Within patients with low CRS (n=349), 9.17% had a high GRS, compared to 8.93% in patients with low RRS (n=280). In patients with grade 1 histology (n=130), 3.85% had a high GRS and 68.46% had tumors &gt; 1cm, of whom only 4.49% had a high GRS. Tumor size &gt; 1cm did not associate with a high GRS (Fisher’s Exact test; P=1.00). Conclusions: In patients with early HR+/ ERBB2- BC, &lt;10% of patients with low clinical risk, and &lt;5% of patients with grade 1 tumors, had a high genomic recurrence risk, respectively. Given current NCCN recommendation for testing, our findings raise the question of whether genomic testing for patients with grade 1 tumors can be safely omitted, irrespective of size, and call for a better understanding of the need for routine genomic testing in patients with low grade/low clinical risk of recurrence. [Table: see text]
When can we de-intensify treatments in ISUP Grade Group 5 prostate cancer? Long-term results of a single center, high volume series
Authors: S.L.A. Scuderi, G.O. Cirulli, F. Barletta, M. De Angelis, L. Toneatto, E. Mazzone, A. Stabile, A. Gallina, N. Fossati, E. Zaffuto, F. Dehò, U. Capitanio, A. Larcher, A. Salonia, G. Gandaglia, S. Shariat, P.I. Karakiewicz, F. Montorsi, A. Briganti
Journal: European Urology (2022)
Adjuvant icotinib versus observation in patients with completely resected, EGFR-mutated, stage IB non–small cell lung cancer (GASTO1003, CORIN): A randomized phase II trial.
Authors: Ning Li, Bao-Xiao Wang, Wei Ou, Hena Shi, Dong Ji, Yan Yan, Shu-Quan Wang, Wu-Guang Chang, Teng-Fei Zhu, Si-Yu Wang
Journal: Journal of Clinical Oncology (2022)

8519 Background: The role of adjuvant therapy in patients with completely resected stage IB non-small-cell lung cancer (NSCLC) remains to be determined. Icotinib is standard-of-care therapy for patients with advanced NSCLC harboring epidermal growth factor receptor (EGFR) mutation. This phase II study investigated whether adjuvant therapy with icotinib improves the clinical outcome compared with observation in patients with EGFR mutation-positive resected stage IB NSCLC. Methods: This phase II, open-label, randomized study (GASTO1003, CORIN) was conducted at Sun Yat-sen University Cancer Center. From May 2013 to December 2020, patients with completely resected, EGFR mutation-positive, stage IB (7th TNM staging for NSCLC) NSCLC without adjuvant chemotherapy according to physician and patient choices were enrolled. The patients were assigned in a 1:1 ratio to receive adjuvant therapy with icotinib (125mg, three times daily) for 12 months or to undergo observation. Therapy continued until disease progression or intolerable toxicity. The primary endpoint was disease-free survival (DFS). Secondary endpoints included overall survival (OS) and toxicity. Survival endpoints were assessed in the intention-to-treat population. Results: Three patients withdrew consent and were excluded. A total of 128 patients were enrolled and randomized, with 63 patients in the icotinib group and 65 patients in the observation group. Baseline characteristics were well balanced between the groups. The median duration of follow-up was 34.9 months. A total of 13 recurrence events occurred, including 2 in the icotinib arm and 11 in the observation arm. DFS was significantly longer among those in the icotinib arm than among those in the observation arm (hazard ratio: 0.20, 95% confidence interval, 0.04-0.89; P = 0.018). The 3-year DFS for the icotinib and observation arms were 95.3% and 86.7%, respectively. The OS data were immature with 3 deaths in the observation arm. The safety profile was consistent with the known safety profile of icotinib. Icotinib was well tolerated with no unexpected adverse events. No treatment-related death occurred. Conclusions: Adjuvant icotinib shows prolonged DFS and acceptable toxicity in patients with completely resected EGFR-mutated stage IB NSCLC. Ajuvant icotinib provides a treatment option for these patients. Clinical trial information: NCT02264210.
Analysis of plasma angiogenesis factors on the efficacy of first-line (1L) chemotherapy (chemo) combined with biologics in <i>RAS</i> wild-type metastatic colorectal cancer (mCRC): Results from GI-SCREEN CRC Ukit study.
Authors: Satoshi Yuki, Yu Sunakawa, Kentaro Yamazaki, Hiromichi Shirasu, Hiroya Taniguchi, Toshiki Masuishi, Manabu Shiozawa, Hideaki Bando, Tomohiro Nishina, Hisateru Yasui, Takashi Ohta, Naoki Takahashi, Tadamichi Denda, Taito Esaki, Hisato Kawakami, Hironaga Satake, Atsuo Takashima, Yukiko Abe, Shogo Nomura, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2022)

3530 Background: Angiogenesis factors have been reported as prognostic and predictive biomarkers of angiogenesis inhibitors for mCRC (Weickhardt AJ. Br J Cancer 2015. Tabernero J. Ann Oncol 2018). We investigated whether plasma angiogenesis factors could predict the efficacy of biologics combined with chemo in 1L treatment in patients (pts) with RAS wild-type mCRC. Methods: Serial plasma samples were prospectively collected at the time points of pre- and post-treatments in mCRC pts receiving biologics in either 1L or 2nd-line (2L) chemo. From Sep 2017 to Dec 2020, 497 pts were enrolled [1L chemo plus bevacizumab (1L BEV, n=102), 1L chemo plus anti-EGFR antibody (1L aEGFR, n=100), 2L chemo plus bevacizumab (n=100), 2L FOLFIRI plus RAM (n=99), 2L FOLFIRI plus aflibercept (n=85) and other treatment (n=11)]. Total of 17 plasma angiogenesis factors (HGF, PlGF, VEGF-A, VEGF-D, Angiopoietin-2, IFN-γ, IL-6, IL-8, sNeuropilin-1, TSP-2, OPN, sVEGFR1, sVEGFR2, sVEGFR3, sICAM-1, sVCAM-1, and TIMP-1) were analyzed by the multiplex assay with Luminex ® technology. Interactions of their pre-treatment measurements with treatment groups on PFS and OS were assessed via Cox proportional hazards model. The strength of interactions was estimated using a propensity score weighting analysis, and the continuous plasma angiogenesis variables were categorized according to the median. The significance level in the interaction was defined as p≤0.1. Results: 133 pts were included in adjusted RAS wild-type 1L cohort (1L BEV: n=33, 1L aEGFR [reference]: n=100). Baseline characteristics of adjusted RAS wild-type 1L cohort were as follows; median age 64 years; male 62.4%; left-sided tumor 88.7%; triplet chemo 15.0%. Propensity-score weighted Cox model for OS showed significant interactions in IL-8 (median 8.03 pg/mL, high: HR 1.738, p=0.0838, Low: HR 0.479, p=0.2624, interaction p=0.0283), sVEGFR-1 (median 1,350 pg/mL, high: HR 0.333, p=0.1770, Low: HR 1.311, p=0.3004, interaction p=0.0777), and sVCAM-1 (median 1,020,000 pg/mL, high: HR 0.100, p=0.0558, Low: HR 1.616, p=0.1765, interaction p=0.0011). In terms of PFS, there were significant interactions in IL-8 (high: HR 1.322, p=0.0418, Low: HR 0.517, p=0.0528, interaction p=0.0752) and sVCAM-1 (high: HR 0.285, p=0.0414, Low: HR 1.200, p=0.7725, interaction p=0.0156). Conclusions: Pre-treatment plasma IL-8 and sVCAM-1 could be predictive biomarkers for efficacy of biologics combined with chemo in 1L treatment of RAS wild-type mCRC. Clinical trial information: UMIN000028616. [Table: see text]
Change in serial liver stiffness measurement by magnetic resonance elastography and outcomes in NAFLD
Authors: Tolga Gidener, Ross A. Dierkhising, Kristin C. Mara, Terry M. Therneau, Sudhakar K. Venkatesh, Richard L. Ehman, Meng Yin, Alina M. Allen
Journal: Hepatology (2022)

Background and Aims: The impact of disease progression in NAFLD on liver outcomes remains poorly understood. We aimed to investigate NAFLD progression using longitudinal liver stiffness measurements (LSM) by serial magnetic resonance elastography (MRE) and the association with liver outcomes. Approach and Results: All adult patients with NAFLD who underwent at least two serial MREs for clinical evaluation at Mayo Clinic, Rochester, between 2007 and 2019 were identified from the institutional database. Progression and regression were defined based on LSM change of 19% above or below 19% of initial LSM, respectively, based on Quantitative Imaging Biomarker Alliance consensus. The association between change in LSM and liver‐related outcomes occurring after the last MRE was examined using time‐to‐event analysis. A total of 128 participants underwent serial MREs (53% female, median age 59 years). The median time between paired MREs was 3.4 (range 1–10.7) years. NAFLD progression (LSM = +0.61 kPa/year) was identified in 17 patients (13.3%). NAFLD regression (−0.40 kPa/year) occurred in 35 patients (27.3%). Stable LSM was noted in 76 participants (59.4%). In NAFLD without cirrhosis at baseline ( n = 75), cirrhosis development occurred in 14% of LSM progressors and 2.9% of non‐progressors ( p = 0.059) over a median 2.7 years of follow‐up from the last MRE. Among those with compensated cirrhosis at baseline MRE ( n = 29), decompensation or death occurred in 100% of LSM progressors and 19% of non‐progressors ( p &lt; 0.001) over a median 2.5 years of follow‐up after the last MRE. Conclusions: Noninvasive monitoring of LSM by conventional MRE is a promising method of longitudinal NAFLD monitoring and risk estimation of liver‐related outcomes in NAFLD.
Pan-cancer analysis of YAP1 expression as a predictive biomarker for cancer immunotherapy.
Authors: Taofeek K. Owonikoko, Andrew Elliott, Andrey Ivanov, Bhakti Dwivedi, Phillip Walker, Ari M. Vanderwalde, Sonam Puri, Sanja Dacic, Daniel Morgensztern, Stephen V Liu, Hossein Borghaei, Gabriel Sica
Journal: Journal of Clinical Oncology (2022)

2629 Background: High YAP1 expression correlates with the ‘T-cell inflamed’ expression phenotype in small cell lung cancer (SCLC), but its association with other biomarkers of immune checkpoint vulnerability and in tumor types beyond SCLC is not known. We examined whether YAP1 expression correlates with other established markers of immune checkpoint blockade (ICB) efficacy (PDL1 expression and TMB) in a tumor agnostic manner to determine clinical relevance. Methods: Next-generation sequencing of DNA (592 gene panel or whole exome) and RNA (whole transcriptome) was performed for patient samples (n = 57,134), representing 13 cancer types, submitted to a CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ). The ‘T-cell inflamed’ signature (TIS) score was calculated as an 18-gene weighted coefficient composite value (Cristescu, 2018). PDL1 expression was assessed by immunohistochemistry (IHC) with cancer type-specific antibodies and thresholds, and high tumor mutational burden was defined as ≥10 mut/Mb. Patients were stratified into subgroups based on median YAP1 expression (YAP1-High/YAP-Low) within each cancer type. Significance was tested by Chi-square, Fisher’s exact test, or Mann-Whitney U test. Results: YAP1-High tumors were associated with significantly increased TIS scores compared to YAP1-Low across all 13 cancer types examined, with the largest fold increase observed in SCLC (1.33-fold, p &lt; 0.0001), followed by pancreatic cancer (1.28-fold, p &lt; 0.0001), while the smallest occurred in melanoma (1.13-fold, p &lt; 0.0001). Spearman correlation strength (range 0.23-0.57) between YAP expression and TIS scores was consistent with increased TIS scores in YAP1-High samples. TMB-High rates were similar in YAP-High and YAP1-Low subgroups for most cancer types, with slightly lower rates in YAP1-High tumors observed for endometrial (23.0 vs 26.6%, p &lt; 0.001) and esophageal (7.0 vs 9.5%, p &lt; 0.05) cancers. YAP1 expression was not significantly increased in PDL1+ (IHC) tumors for most cancer types. However, significantly decreased YAP1 expression was associated with PDL1+ samples in RCC (Renal Cell Carcinoma) (0.91-fold change, P &lt; 0.05), MM (0.90-fold change, P &lt; 0.001), and ENCA (0.80-fold change, P &lt; 0.0001) Conclusions: Our analyses provide confirmation that YAP1 expression positively correlates with the ‘T-cell inflamed’ phenotype across many cancer types, including those with approvals for (ICB) therapy. YAP1 expression was independent of established markers of ICB response, including TMB and PDL1. Further analysis of YAP1 expression as an additional tumor agnostic predictive biomarker is warranted.
Efficacy and safety of eribulin in the treatment of advanced adult soft tissue sarcoma (STS): First real-world data in Chinese population.
Authors: Xi Guo, Yuhong Zhou, Rongyuan Zhuang, Yang You, Chenlu Zhang, Zhiming Wang
Journal: Journal of Clinical Oncology (2022)

11577 Background: Eribulin has shown efficacy in STS, especially for the L-type sarcomas, including liposarcoma (LPS) and leiomyosarcoma (LMS). We investigated the efficacy and safety of eribulin in the treatment of advanced adult STS in Chinese population. Methods: The study retrospectively analyzed data from patients diagnosed as advanced STS and received eribulin monotherapy or combination regimens in the Department of Oncology, Zhongshan Hospital affiliated to Fudan University from January 2020 to February 2021. Primary endpoint was objective response rate (ORR) by RECIST v1.1. Secondary endpoints included disease control rate (DCR), progress-free survival (PFS) and treatment-related adverse events (TRAE) by CTCAE v5.0. Results: A total of 40 patients who received at least two doses of eribulin and underwent at least one post-baseline response assessment were included in analysis. The mean age was 48 years. 82.5% (33/40) had L-type sarcomas, and 17.5% (7/40) had non-L-type sarcomas. Overall, 25% (10/40) of patients received eribulin alone; and 75% (30/40) received combination regimens. Drugs used with eribulin included gemcitabine, tyrosine kinase inhibitors (TKIs), anti-PD-1 antibodies, or TKIs plus anti-PD-1 antibodies. For the 40 patients, the ORR was 27.5% (11/40) and the DCR was 60% (24/40). The ORR for myxoid liposarcoma was especially encouraging: 54.5% (6/11) and the DCR was 72.7% (8/11). 10 patients received the combined therapy of anti-PD-1 antibodies, TKIs, and eribulin and showed a likely better ORR of 30% (3/10) and DCR of 70% (7/10). After a median follow-up time of 12.57 months (IQR, 8.43-16.30), the median PFS was 4.13 months (95% CI, 2.17-8.40). 10 out of 33 (30.3%) patients with L-type sarcomas had achieved PR and the median PFS was 4.45 months, 1 out of 7 (14.3%) patients with non-L-type sarcomas had achieved PR and the median PFS is 2.67 months. Common TRAEs were bone marrow suppression (42.5%), hypertriglyceridemia (25%), fatigue (10%), hypertension (7.5%). No treatment-related death happened. Logistic regression analysis of the multiple factors influencing ORR revealed no difference between taxane-treated and taxane-naïve patient groups. Conclusions: This study presents the first real-world data on the use of eribulin in STS in Chinese population. Eribulin monotherapy or combination therapy were likely more effective in this population, as well-tolerated as with Study 309, especially in treating liposarcoma. Eribulin used in combination with TKI and anti-PD-1 antibody showed potential efficacy in STSs. Further clinical exploration of front-line eribulin monotherapy and combination strategies in this setting is warranted.
Design and rationale of a phase 1 dose-escalation study of AMG 193, a methylthioadenosine (MTA)-cooperative PRMT5 inhibitor, in patients with advanced methylthioadenosine phosphorylase (MTAP)-null solid tumors.
Authors: Miguel Angel Villalona-Calero, Amita Patnaik, Robert G Maki, Bert O'Neil, James L. Abbruzzese, Ibiayi Dagogo-Jack, Siddhartha Devarakonda, Sara Wahlroos, Chia-Chi Lin, Yutaka Fujiwara, Angelika Terbuch, Sophie Postel-Vinay, Maria-Elisabeth Goebeler, Alfredo Addeo, Hans Prenen, Tobias Arkenau, Adrian G. Sacher, Chunxu Liu, William Kormany, Jordi Rodon Ahnert
Journal: Journal of Clinical Oncology (2022)

TPS3167 Background: Protein arginine methyltransferase 5 (PRMT5) is an emerging target for cancer treatment. MTAP homozygous deletion occurs in 15% of cancers and often coincides with deletion of the tumor suppressor gene CDKN2A, leading to buildup of its substrate MTA. MTA shares close structural similarity to S-adenosyl methionine (SAM), the substrate methyl donor for PRMT5. By competing with SAM, MTA partially inhibits PRMT5. Thus, MTAP-null cancers are susceptible to further PRMT5 inhibition (Kryukov Science 2016). Current direct/indirect PRMT5 inhibitors (PRMT5i) showed preliminary anticancer activity, albeit with considerable toxicities due to their indiscriminate activities. AMG 193 is an MTA-cooperative PRMT5i that preferentially targets the MTA-bound state of PRMT5 that is enriched in MTAP-null tumors and represents a novel strategy to increase the therapeutic margin of this class of inhibitors. AMG 193 potently inhibits MTAP-null cancer cell lines and patient-derived xenografts. Methods: NCT05094336 is a first-in-human (FIH), multicenter, open-label, phase 1/1b/2 trial evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and efficacy of AMG 193 in patients with advanced MTAP-null solid tumors. Eligible patients (≥ 18 years) with histologically confirmed locally advanced/metastatic solid tumors not amenable to curative treatment with surgery and/or radiation, homozygous MTAP and/or CDKN2A deletion (by local next generation sequencing), or MTAP protein loss in tumors (by central immunohistochemistry), measurable disease, ECOG PS 0‒1, adequate hematopoietic, renal, liver, pulmonary, cardiac, coagulation function and glucose control will be included. The study will be conducted in 3 parts, each with subparts. Here, we describe Part 1a/b (dose exploration). Five dose levels are planned. Treatment continues until progression or withdrawal. The primary objectives are to evaluate the safety and tolerability of AMG 193 monotherapy; endpoints include dose-limiting toxicities, treatment-emergent adverse events, serious adverse events, electrocardiograms, laboratory abnormalities, and vital signs. Secondary objectives include the characterization of the PK parameters of AMG 193 including C max , T max , and AUC after single or multiple doses. This study is expected to enroll approximately 30 patients in Part 1a/b. This is the first FIH trial open for enrollment for this new class of PRMT5i and enrollment is ongoing. Clinical trial information: NCT05094336.
Predictors of differential outcomes according to response to induction chemotherapy in high-risk neuroblastoma.
Authors: Elizabeth Sokol, Brian LaBarre, Arlene Naranjo, Navin R. Pinto, Susan G. Kreissman, Meaghan Granger, Julie R. Park, Rochelle Bagatell, Steven G. DuBois
Journal: Journal of Clinical Oncology (2022)

10032 Background: Response to induction chemotherapy has been shown to predict outcome in patients with high risk neuroblastoma, with those achieving a complete response (CR) having superior outcomes. Little is known about what factors impact survival within groups of patients with favorable and unfavorable end-induction response. We evaluated whether conventional prognostic factors remain prognostic in subsets of patients defined by response to induction. Methods: Patients from four COG high risk trials (A3973, ANBL02P1, ANBL0532, and ANBL12P1) were included. End-induction response was determined according to the 1993 International Neuroblastoma Response Criteria (INRC). Patients were categorized as having end-induction responses of CR, partial response (PR) or better, less than PR without progressive disease (PD), and PD. Univariate Cox models calculated OS hazard ratios for clinical and biological variables in subsets defined by response category. Results: 1,244 patients were included. Among all patients, age &gt;5 years, INSS stage 4 disease, adrenal primary site and unfavorable histology by INPC were associated with inferior OS (see Table). Among patients who achieved a CR, stage 4 disease was the only factor that remained significantly associated with worse OS. Among those who achieved PR or better, age &gt;5 years, stage 4 disease and unfavorable histology remained significantly associated with inferior OS. For those with less than PR but without PD, adrenal primary site, MYCN amplification and 1p LOH were significantly associated with inferior OS. For those with PD, MYCN amplification and 1p LOH were associated with worse OS, but older age was associated with better OS. Conclusions: Specific prognostic factors in neuroblastoma are associated with differential survival in groups defined by response to induction. Age, stage, and histology appear to be associated with OS for patients with more favorable response to induction, whereas MYCN and 1p LOH play a greater role in patients with unfavorable response to induction. These data can help to further define prognosis for patients with variable responses to induction. [Table: see text]